Annually, nearly 5,000 extremely low birth weight (ELBW; birth weight =1000 g) infants in the US develop severe (grades III and IV) intraventricular hemorrhage (IVH). Approximately 75% of these infants develop mental retardation and/or cerebral palsy, resulting in profound individual and familial consequences. In addition, lifetime care costs for these severely affected infants born in a single year exceed $3 billion dollars, which emphasizes the financial impact of this major public health problem. The huge individual and societal costs underscore the need for developing care strategies that limit severe IVH. Further, the ability to prospectively predict impending IVH in ELBW infants would enable clinicians and researchers to intervene before IVH occurs and possibly decrease the incidence of adverse neurodevelopmental sequelae. Therefore, the long-term goal of our patient-oriented clinical research is to prospectively evaluate disturbed physiological phenomena associated with cerebral autoregulation and IVH in order to predict those infants most at risk and to develop best care clinical practices that may limit severe brain injuries. While the etiology of IVH is multifactorial, disturbances of cerebral autoregulation play an important role. Increasing hypercapnia has been associated with progressively impaired cerebral autoregulation. Hypotension may cause cerebral hypoperfusion, leading to IVH in infants with impaired cerebral autoregulation by an ischemia/reperfusion mechanism. Autonomic dysfunction may attenuate vasodilatory capacity of cerebral arterioles and impair cerebral autoregulation in ELBW infants. Because disturbances of carbon dioxide, blood pressure, and autonomic function are common in ELBW infants undergoing intensive care, our central hypothesis is that alterations and extremes of these physiological factors that influence cerebral autoregulation in ELBW infants may initiate IVH and serve as important predictors of IVH, thereby allowing identification of a high-risk subgroup of infants who may benefit most from intervention. This hypothesis will be investigated through a series of clinical studies that will address: 1) whether development of IVH in ELBW infants in influenced by permissive hypercapnia, 2) whether impaired cerebral autoregulation in hypotensive ELBW infants is restored when BP is normalized with dopamine and whether autoregulatory capacity is influenced by hypercapnia, and 3) whether impending IVH may be predicted by altered autonomic function in ELBW infants. We will use our continuous physiological monitoring system developed during our K23 studies to determine cerebral autoregulatory capacity. Heart rhythm dynamics on the first day of life will be determined and its value as a predictor of impending IVH will be evaluated. If successful, our proposed clinical studies will reduce the burden of neurological disease in newborn ELBW infants by developing better care clinical practices and by providing a new accurate predictor of impending IVH, so that high-risk infants may be identified and interventions applied to limit development of IVH. PUBLIC HEALTH RELEVANCE Annually, almost 5,000 extremely low birth weight (<2 lbs, 3 ounces) infants born in the US survive with severe bleeding in the brain (intraventricular hemorrhage); this devastating complication of prematurity is associated with long-term neurological problems, including mental retardation, cerebral palsy, and behavioral and learning disabilities. Lifetime care costs for these severely affected infants born in a single year exceed $3 billion, which emphasizes the financial impact of this major public health problem. The overall goal of our research is to evaluate disturbances of brain blood flow regulation in these tiny infants in order to predict which are at highest risk and to develop better intensive care techniques that will limit severe brain injury.